Submissions for variant NM_080425.4(GNAS):c.538C>T (p.Gln180Ter)

gnomAD frequency: 0.00008  dbSNP: rs200910410

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV002504569	SCV002815236	uncertain significance	McCune-Albright syndrome; Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pituitary adenoma 3, multiple types; ACTH-independent macronodular adrenal hyperplasia 1; Pseudohypoparathyroidism type I A	2022-05-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354116	SCV001548652	uncertain significance	Pseudohypoparathyroidism type 1B		no assertion criteria provided	clinical testing	The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354967	SCV001549705	uncertain significance	Progressive osseous heteroplasia		no assertion criteria provided	clinical testing	The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357204	SCV001552594	uncertain significance	Pseudohypoparathyroidism type 1C		no assertion criteria provided	clinical testing	The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358585	SCV001554366	uncertain significance	Pseudopseudohypoparathyroidism		no assertion criteria provided	clinical testing	The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358646	SCV001554440	uncertain significance	Pseudohypoparathyroidism		no assertion criteria provided	clinical testing	The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics, Academic Medical Center	RCV001698589	SCV001917030	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001698589	SCV001951138	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001698589	SCV001971780	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004531152	SCV004116541	uncertain significance	GNAS-related disorder	2024-04-24	no assertion criteria provided	clinical testing	The GNAS c.538C>T variant is predicted to result in premature protein termination (p.Gln180*). In the primary transcript of the GNAS gene (NM_000516.5), this variant is located in the 5’ untranslated region (UTR) and is defined as c.-37924C>T. To our knowledge, this variant has not been reported in the literature. At PreventionGenetics, we have observed the c.538C>T variant in a patient with abnormal thyroid function and a profile that suggested resistance to thyroid hormone. This variant was inherited from the unaffected father who was apparently mosaic for the c.538C>T variant. Although truncating variants in GNAS are a known mechanism of disease, these variants are all reported in the primary transcript (NM_000516.5). The c.538C>T variant is located in exon 1 of transcript NM_080425.3 and, to our knowledge, no other protein truncating variants have been reported in this exon (Human Gene Mutation Database). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.